Cbl and Itch binding sites in ERBB4 CYT-1 and CYT-2 mediate K48- and K63-polyubiquitination, respectively

Meijer, Inez M.J.; Rotterdam, Walter van; Zoelen, E.J.J. van; Leeuwen, Jeroen E.M. van

doi:10.1016/j.cellsig.2012.11.008

Cited by 15 publications

(16 citation statements)

References 62 publications

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“…Although mRNA levels for FL CYT-1 and CYT-2 were comparable (Fig 1B), CYT-2 ERBB4 protein was slightly higher at steady state, and this difference was augmented by stimulation with NRG1 (Figure 1C). This is consistent with the reports that CYT-2 protein is more stable, since it lacks the ubiquitin-ligase binding site present in CYT-1 (27, 28). …”

Section: Resultssupporting

confidence: 93%

Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells

Wali

Haskins

Gilmore-Hebert

et al. 2014

Molecular Cancer Research

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Associations of ErbB4 (ERBB4/HER4), the fourth member of the EGFR family, with cancer are variable, possibly as a result of structural diversity of this receptor. There are multiple structural isoforms of ERBB4 arising by alternative mRNA splicing, and a subset undergo proteolysis that releases membrane-anchored and soluble isoforms that associate with transcription factors and co-regulators to modulate transcription. In order to compare the differential and common signaling activities of full-length and soluble intracellular isoforms of ERBB4, four JM-a isoforms (full-length and soluble intracellular domain CYT-1 and CYT-2) were expressed in isogenic MCF10A cells and their biological activities were analyzed. Both full-length and intracellular domain CYT-2 promoted cell proliferation and invasion, and CYT-1 suppressed cell growth. Transcriptional profiling revealed several new and underexplored ERBB4 regulated transcripts including: proteases/protease inhibitors (MMP3, SERPINE2), YAP/Hippo pathway (CTGF, CYR61, SPARC), mevalonate/cholesterol pathway (HMGCR, HMGCS1, LDLR, DHCR7), and cytokines (IL8, CCL20, CXCL1). Many of these transcripts were subsequently validated in a luminal, breast cancer cell line that normally express ERBB4. Furthermore, ChiP-seq experiments identified ADAP1, APOE, SPARC, STMN1, and MXD1 as novel molecular targets of ERBB4. These findings clarify the diverse biological activities of ERBB4 isoforms, and reveal new and divergent functions.

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Section: Resultssupporting

confidence: 93%

Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells

Wali

Haskins

Gilmore-Hebert

et al. 2014

Molecular Cancer Research

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“…25 Expression of Itch-C830A with WT ubiquitin did not lead to ubiquitination of HIC-5 ( Figure 4a). Since Itch targets its substrates for polyubiquitination via Lys27 (K27)-, K29-, K33-, K48-, and K63-linked ubiquitin chains, [26][27][28][29][30] we sought to identify the linkage of the Itchmediated ubiquitination of HIC-5 by using the ubiquitin expression constructs HA-Ub-K48, HA-Ub-K63, HA-Ub-K6, HA-Ub-K0, HA-Ub-K11, HA-Ub-K27, HA-Ub-K29, and HA-Ub-K33 (in which all of the lysine residues except K48, K63, K6, K0, K11, K27, K29, and K33, respectively, are replaced). As shown in Figure 4b and Supplementary Figure 3, Itch predominantly targeted HIC-5 for K63-linked ubiquitination.…”

Section: Itch Targets Hic-5 For K63-linked Ubiquitinationmentioning

confidence: 99%

IL-17-driven intestinal fibrosis is inhibited by Itch-mediated ubiquitination of HIC-5

et al. 2018

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Intestinal fibrosis is a major complication in inflammatory bowel diseases, but the regulatory mechanism that inhibits fibrosis remains unclear. Here we demonstrate that Itchmyofibroblasts express increased amounts of profibrotic collagen type I and α-SMA in response to IL-17. Mechanistically, we demonstrate that Itch directly binds to HIC-5 and targets it for K63-linked ubiquitination to inhibit IL-17-driven intestinal fibrosis. Reconstitution of Itch myofibroblasts with wild-type Itch but not the Itch-C830A mutant normalized the expression of profibrotic genes. Similarly, shRNA-mediated inhibition of HIC-5 normalized the expression of profibrotic gene expression. Thus, we have uncovered a novel mechanism by which Itch negatively regulates intestinal fibrosis.

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“…Furthermore, our earlier work showed the involvement of the E3 ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) and its homologue c-Cbl in TRAIL-triggered gastric cancer cell apoptosis (Xu et al, 2009(Xu et al, , 2012. Given that c-Cbl is required for EGF-induced K48-linked polyubiquitination of ERBB4 cytoplasmic isoforms (Meijer et al, 2013), we therefore investigated whether Cbl-b and c-Cbl were components of a complex that regulates caspase-8 polyubiquitination and hence influence the sensitivity of gastric cancer cells to TRAIL.…”

Section: Introductionmentioning

confidence: 99%

DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibits TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells

Zhang

et al. 2017

Molecular Oncology

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Ubiquitination of caspase‐8 regulates TNF‐related apoptosis‐inducing ligand (TRAIL) sensitivity in cancer cells, and the preligand assembly complex plays a role in caspase‐8 polyubiquitination. However, whether such a complex exists in gastric cancer cells and its role in TRAIL‐triggered apoptosis is unclear. In this study, DR5, casitas B‐lineage lymphoma‐b (Cbl‐b)/c‐Cbl, and TRAF2 formed a complex in TRAIL‐resistant gastric cancer cells, and Cbl‐b and c‐Cbl were the critical adaptors linking DR5 and TRAF2. Treatment with TRAIL induced caspase‐8 translocation into the DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex to interact with TRAF2, which then mediated the K48‐linked polyubiquitination of caspase‐8. The proteasome inhibitor bortezomib markedly enriched the p43/41 products of caspase‐8 activated by TRAIL, indicating proteasomal degradation of caspase‐8. Moreover, TRAF2 knockdown prevented the polyubiquitination of caspase‐8 and thus increased TRAIL sensitivity. In addition, the inhibition of Cbl‐b or c‐Cbl expression and overexpression of miR‐141 targeting Cbl‐b and c‐Cbl partially reversed TRAIL resistance by inhibiting the interaction between TRAF2 and caspase‐8 and the subsequent polyubiquitination of caspase‐8. These results indicate that the DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibited TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells.

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Cbl and Itch binding sites in ERBB4 CYT-1 and CYT-2 mediate K48- and K63-polyubiquitination, respectively

Cited by 15 publications

References 62 publications

Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells

Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells

IL-17-driven intestinal fibrosis is inhibited by Itch-mediated ubiquitination of HIC-5

DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibits TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells

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